The objective of this proposal is to provide the applicant with exemplary research training in skeletal biology. To achieve this objective, a training regimen focused upon synovial joint morphogenesis has been developed, consisting of research aims and substantial training activities. Synovial joints are essential for skeletal function and quality of life and much is known about their anatomical organization, distinct tissues and susceptibility to common pathologies including age-dependent osteoarthritis. In contrast, very little is known about their developmental biology. Were such information available, it could be used directly or in combination with bioengineering tools to create new joint repair and regenerative strategies such as engineered stem cells with specific joint tissue-formation capacity; these strategies could counter the notoriously poor intrinsic repair capacity of joint tissues. Our central hypothesis for this work is that the early population of multipotent mesenchymal interzone cells at incipient joint sites in the embryonic limb is topographically modulated by the retinoid and Wnt/-Catenin signaling pathways to permit formation of distinct joint tissues over time. Our aims for this fellowship research project are (1) to characterize the roles of retinoid signaling and its interaction with Wnt/-Catenin to regulate interzone cell function and joint tissue formation and (2) to determine interzone cell plasticity and differentiation capacity during joint development as well as in repair of mature joint tissues in postnatal animals. The project outlined in the proposal combines work of fundamental basic research importance with work directed toward the future creation of novel cell-, pharmacologic- or gene-based therapies for joint disease in the affected or elderly population. Overall, the project represents a balanced and effective training regimen to allow the applicant to fully develop the technical and intellectual skills needed to establish a successful and independent research program in the future.